WO2025096300A1 - Novel methods for the preparation of 3-azabicylco[3.1,0]hexane-6-carboxamide derivatives - Google Patents

Abstract

Methods for preparing 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives, which can be useful as SSTR4 agonist compounds. Methods for preparing 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives through a rhodium catalyzed cyclopropanation reaction with alkyl diazoacetate under low catalyst loadings. Methods for preparing 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives including a isomerization step and/or a selective hydrolysis step. Methods for preparing an intermediate compound through a rhodium catalyzed cyclopropanation reaction with alkyl diazoacetate under low catalyst loadings, which can be useful in the preparation of a variety of 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives.

Description

NOVEL METHODS FOR THE PREPARATION OF 3- AZABICYLCO[3.1.0]HEXANE-6-CARBOXAMIDE DERIVATIVES

FIELD OF THE INVENTION

[0001] The present invention is directed to novel methods for the preparation of 3- azabicyclo[3.1.0]hexane-6-carboxamide derivatives, which can be useful as SSTR4 agonists. The present invention is also directed to novel methods for the preparation of an intermediate compound, which can be used for the preparation of 3- azabicyclo[3.1.0]hexane-6-carboxamide derivatives.

BACKGROUND OF THE INVENTION

[0002] Somatostatin, or somatotropin-release inhibitory factor (SRIF), is a cyclic peptide found in humans. It is produced widely in the human body and acts both systemically and locally to inhibit the secretion of various hormones, growth factors and neurotransmitters. The effects of somatostatin are mediated by a family of G protein- coupled receptors, of which five subtypes are known. These subtypes are divided into two subfamilies, the first comprising SSTR2, SSTR3 and SSTR5 and the second SSTR1 and SSTR4.

[0003] Somatostatin is involved in the regulation of processes such as for example cellular proliferation, glucose homeostasis, inflammation, and pain. In this aspect, somatostatin or other members of the somatostatin peptide family are believed to inhibit nociceptive and inflammatory processes via the SSTR4 pathway.

[0004] WO 2014/184275 discloses 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives, which are useful as SSTR4 agonists, and which are useful for preventing or treating medical disorders related to SSTR4. However, it can be challenging to synthesize 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives with sufficient enantiomeric and diastereomeric purity. Lab scale synthetic pathways are known, but many steps used in previous synthetic pathways can be impractical and/or too expensive to utilize at commercial scale.

[0005] Thus, there is a need for alternative ways to prepare certain SSTR4 agonists at commercial scale with sufficient purity. Accordingly, the present invention is directed to methods for the preparation of certain SSTR4 compounds, such as 3- azabicyclo[3.1.0]hexane-6-carboxamide derivatives.

[0006] While methods for the preparation of certain SSTR4 compounds are disclosed in WO 2014/184275, WO 2021/233427, and WO 2022/012534, these compounds were produced at laboratory scale, which can include synthetic steps that are impractical at commercial scale. In these previous preparations, the synthetic pathways used high levels of expensive catalysts, including palladium and/or rhodium, which can increase the overall cost of the preparation and add additional purification steps to remove trace amounts of Pd, Rh, and/or undesirable diastereomers with lower activity.

SUMMARY OF THE INVENTION

[0007] Disclosed herein is a method for preparing a compound of the formula or a salt thereof; and the method comprising mixing a compound of the

formul

with a compound of the formula in the presence of from about

0.0001 to about 1 mol% Rh catalyst, wherein A is H or an organic protecting group, X is OH, O- R_x, NH₂, NH(R_x), N(R_x)₂, or a halogen, and R_x is C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens.

[0008] Also disclosed herein is a method for preparing a compound of the formula: or pharmaceutically acceptable salts thereof, wherein Y is a

covalent bond, O, S, C₁ to C₆ ether, or C₁ to C₆ thioether, Z is null, a covalent bond, CH₂, or CH₂CH is an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms

in the heteroaryl or C₆ to C₁₀ aryl, wherein is substituted with one or more R_n, and

Each R_n is independently OH, F, Cl, Br, I, NH₂, CF₃, C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, C₁ to C₇ ether, or C₁ to C₇ thioether,

the method comprising: (i) mixing a compound of the formula

a compound of

O the formula

in the presence of from about 0.0001 to about 1 mol% Rh catalyst to form an intermediate compound of the formula

salt thereof, wherein A is H or an organic protecting group, X is OH, O-R_x, NH₂, NH(R_x), N(R_x)₂, or a halogen, and R_x is C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens;

(ii) mixing the intermediate compound with

to yield

[0009] Also disclosed herein is a method for preparing a compound of the formula:

pharmaceutically acceptable salts thereof, using the methods described herein.

[0010] Also disclosed herein is a method for preparing a compound of the formula

pharmaceutically acceptable salts thereof, using the methods described herein. [0011] Also disclosed herein is a method for preparing a compound of the formula

formula

a compound of the formula

in the presence of from about

0.0001 to about 1 mol% Rh catalyst, wherein A is H or an organic protecting group, X is OH, O-R_x, NH₂, NH(R_x), N(R_x)₂, or a halogen, and R_x is C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens.

[0012] Also disclosed herein is a compound of the formula:

salt thereof, and wherein A is H or an organic protecting group.

[0013] Also disclosed herein is a method for preparing a compound of the formula:

salt thereof, the method comprising: mixing a compound of the formula

a compound of the formula in the presence of from about 0.0001 to about 1 mol% Rh catalyst,

wherein A is H or an organic protecting group,

X is OH, O-R_x, NH₂, NH(RX), N(R_x)₂, or a halogen, and

R_x is C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens. DETAILED DESCRIPTION OF THE INVENTION

[0014] Disclosed herein, is a new stereoselective route to certain SSTR4 compounds, such as 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives, which can be performed at commercial scale with minimal use of a Rh metal catalyst to form the intermediate disclosed in Formula XL

[0015] Disclosed herein, is a composition comprising a stereochemically pure intermediate, the exo stereoisomer as shown in Formula XII, can be isolated with an isomerization step without the need for any chromatography purification steps. Additionally disclosed herein, is a composition comprising a stereochemically pure intermediate, the endo stereoisomer as shown in Formula XII, which can be isolated through the selected hydrolysis of the exo stereoisomer followed by extraction without the need for any chromatography purification steps.

[0016] Also disclosed herein is a method for the preparation of a variety of

SSTR4 agonist compounds with an amidation reaction between a compound comprising an amine and the stereochemically pure intermediate compound in the exo or endo stereoisomers, as shown in Formula XI and XII.

[0017] Certain abbreviations are as follows: “I” refers to acetonitrile; “Boe” refers to tert-butyloxycarbonyl; “BTMG” refers to 2-tert-buty1-1,1,3,3-tetramethylguanidine; “cbz” refers to carbobenzyloxy; “DBU” refers to l,8-diazabicyclo(5.4.0)undec-7-ene “DCM” refers to dichloromethane; “DMAP” refers to 4 -dimethylaminopyridine; DMC refers to dimethyl carbonate; “EtOH” refers to ethanol; “equiv” refers to equivalent; “Fmoc” refers to fluorenylmethyloxy carbonyl; “hr/hrs” refers to hour/s; “KOtBu” refers to potassium tert- butoxi de; MeOH refers to methanol; “min” refers to minute/s; “NaOtBu” refers to sodium tert-butoxide; “TBD” refers to triazabicyclodecene; and “THF” refers to tetrahydrofuran.

SSTR4 Agonists

[0018] The disclosed method can be used to prepare the compounds of Formula I or Formula II, wherein Z can be null, a covalent bond, CH₂, or CH₂CH₂, Y can be covalent bond, O, S, C₁ to C₆ ether, or C₁ to C₆ thioether,

is an 8-member to 10- member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C₆ to C₁₀ aryl,

can be substituted with one or more R_n, and each R_n can be independently OH, F, Cl, Br,

I, NH₂, CF₃, C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, C₁ to C₇ ether, C₁ to C₇ thioether, or combinations thereof.

[0019] The disclosed method can also be used to prepare salts, pharmaceutically acceptable salts, solvates, hydrates, and/or combinations thereof of Formula I or Formula

II.

[0020]

, as described herein, can be a C₆ to C₁₀ aryl or a 5-member to 10- member heteroaryl with from 1 to 4 heteroatoms selected from O, N, or S.

[0021] In some embodiments,

can be an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms selected from O, N, or S.

( A ) [0022] In some embodiments, can be a monocyclic, bicyclic, or polycyclic system.

is a monocyclic system,

can be a C₅ to C₆ aryl or five-member to six-member heteroaryl with 1 or 2 heteroatoms selected from O, N, or S.

is a bicyclic system, each of the ring systems can include a C₅ to C₆ aryl or five-member to six-member heteroaryl with 1 or 2 heteroatoms selected from O, N, or S. [0023] In some embodiments,

can be substituted with one or more R_n. R_n ca be independently selected from OH, F, Cl, Br, I, NH₂, C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, C₁ to C₇ ether, C₁ to C₇ thioether, or combinations thereof.

[0024] In some embodiments, n can represent the number of substitutions on For example, Ri can be a first substitution on

m R₂ can be a second

substitution on , etc.

[0025] In some embodiments, Y can be covalent bond, O, S, C₁ to C₆ ether, or C₁ to C₆ thioether. When Y is null, is connected via a covalent bond to the dimethyl

substituted carbon atom immediately adjacent to the amide functional group.

[0026] In some embodiments Z can be null, a covalent bond, CH₂, or CH₂CH₂. When Z is null, there no connection between the two methyl substituents at the alpha carbon atom. When Z is a covalent bond, the alpha carbon atom forms a cyclopropyl functional group. When Z is CH₂, the alpha carbon atom forms a cyclobutyl functional group. When Z is CH₂CH₂, the alpha carbon atom forms a cyclopentyl functional group.

[0027] In some embodiments, the C₁ to C₇ thioether can be a thioether selected from Formula III.

[0028] The disclosed method can be used to prepare the compounds of Formula IV. The disclosed method can also be used to prepare solvates, hydrates, and/or combinations thereof of Formula IV and/or Formula V.

Formula IV. SSTR4 Agonists that can be made by the disclosed method.

Formula V. Additional SSTR4 Agonists that can be made by the disclosed methods

Methods

[0029] Disclosed herein are novel methods for the preparation of 3- azabicyclo[3.1.0]hexane-6-carboxamide derivatives, which can be useful as SSTR4 agonist compounds. Suitable 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives can be prepared using a Rh catalyzed cyclopropanation reaction with alkyl diazoacetate to form an intermediate compound (step (i)), mixing the intermediate compound with an amine to form an SSTR4 agonist compound (step (ii)), and removal of an organic protection group, if applicable (step (iii)).

[0030] The novel method can be represented by Formula VI, wherein Z can be null, a covalent bond, CH₂, or CH₂CH₂, Y can be covalent bond, O, S, C₁ to C₆ ether, or C₁ to C₆ thioether,

is an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C₆ to C₁₀ aryl,

can be substituted with one or more R_n, and each R_n can be independently OH, F, Cl, Br, I, NH₂, CF₃, C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, C₁ to C₇ ether, C₁ to C₇ thioether, or combinations thereof, A can be H or an organic protecting group, such as tert-butyloxycarbonyl (Boc), tosyl (Tos), carbobenzyloxy (Cbz), or fhiorenylmethyloxycarbonyl (Fmoc), X can be OH, O-R_x, NH₂, or a halogen, and R_x can be C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens.

Formula VI.

Step (i) - Rh Catalyzed Cyclopropanation

[0031] Disclosed herein are novel methods to prepare the intermediate compounds of Formula XI and XII using a Rhodium catalyzed cyclopropanation reaction. The Rh catalyzed cyclopropanation can be a [2+1] cycloaddition reaction between a cyclic compound including a double bond and a diazo compound with a carboxyl functional group. The Rh catalyzed cyclopropanation can result in the addition of a cyclopropyl group attached to the original cyclic compound at the position of the double bond.

[0032] In an embodiment, the Rh catalyzed cyclopropanation reaction results in a composition comprising a mixture of the exo stereoisomer and the endo stereoisomer. A stereochemically pure composition comprising only the exo stereoisomer can be obtained from the composition comprising a mixture of stereosiomers through an isomerization reaction, which can be followed by hydrolysis, as further described herein.

[0033] In an embodiment, a stereochemically pure composition comprising only the endo stereoisomer can be obtained from a mixture comprising the exo and endo stereoisomers through selective hydrolysis of the exo stereoisomer, extraction of the endo stereoisomer, and followed by extended hydrolysis of the endo stereoisomer, as further described herein.

[0034] In an embodiment, the cyclic compound including at least one double bond and with zero or one heteroatoms selected from N, S, and O. Suitable cyclic compounds can be selected from Formula VII, wherein A is H or an organic protecting group, such as Tos, Boc, or Cbz.

Formula VII. Cyclic Compounds useful in the Rh catalyzed cyclopropanation (step (i))-

[0035] In an embodiment, the cyclic compound is 1-tosy1-2,5-dihydro-1 H-pyrrole, tert-butyloxycarbonyl 2, 5 -dihydro-1H-pyrrole, or carbobenzyloxy 2,5-dihydro-1H- pyrrole. In an embodiment, the cyclic compound is tert-butyloxycarbonyl 2,5-dihydro- 1H-pyrrole.

[0036] In an embodiment, the diazo compound includes a diazo functional group and a carbonyl functional group. Suitable diazo compounds can be selected from Formula VIII, wherein X can be OH, O-R_x, NH₂, NH-R_x, N(R_x)₂ or a halogen, and R_x is C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens.

Formula VIII. Diazo compounds useful in Rh catalyzed cylcopropanation (step (i))

[0037] In an embodiment, X of Formula VIII can be represented by the compound of Formula VIII-A, wherein Z can be null, a covalent bond, CH₂, or CH₂CH₂, Y can be covalent bond, O, S, C₁ to C₆ ether, or C₁ to C₆ thioether is an 8-member to 10-

member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C₆ to C₁₀ aryl

can be substituted with one or more R_n, and each R_n can be independently OH, F, Cl, Br,

I, NH₂, CF₃, C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, C₁ to C₇ ether, C₁ to C₇ thioether, or combinations thereof and wherein the squiggly line is the portion of the molecule that connects to the carbonyl group present in Formula VIII. When X is represented by the compound of Formula VIII-A, the other portion of the SSTR4 agonist compound can already be attached to the diazo compound, which would allow for step (ii) of the method, as disclosed herein, to be performed prior to the Rh catalyzed cyclopropanation reaction.

[0038] In an embodiment, the diazo compound is alkyl 2-diazoacetate, wherein the alkyl is a C₁-C₆ alkyl.

[0039] In an embodiment, the diazo compound is ethyl 2-diazoacetate.

[0040] The Rh catalyst can be of the formula Rh₂(L)₂ or Rh₂(L)₄, wherein L is any suitable ligand.

[0041] In an embodiment, each L can be a carboxylate derivative.

[0042] In an embodiment, L can be acetate (OAc), pivalate (OPiv), octanoate

(Oct), triphenylacetate (TPA), or 3-[3-(2-carboxy-2-methylpropyl)phenyl]-2,2- dimethylpropanoic acid (esp).

[0043] In an embodiment, the ligand attached to the Rh catalyst can be selected from Formula IX.

[0044] In an embodiment, the Rh catalyst is represented by the compound of Formula X-A, wherein each R_y is independently comprises C₁ to C₁₀ alkyl, C₃ to C₈ cycloalkyl, phenyl optionally substituted with one or more R_z, C₃ to C₈ aryl optionally substituted with one or more R_z, C₃ to C₈ heterocycloalkyl with from 1 to 3 heteroatoms selected from O, S, N, and P and optionally substituted with one or more R_z, C₃ to C₈ heteroaryl with from 1 to 3 heteroatoms selected from O, S, N, and P and optionally substituted with one or more R_z, or combinations thereof. Each R_z can comprise C₁ to C₁₀ alkyl, C₁ to C₅ alkenyl, OH, amine, cyano, C₁ to C₆ alkoxyl, C₃ to C₈ cycloalkyl, C₃ to C₈ aryl, C₃ to C₈ heterocycloalkyl with from 1 to 3 heteroatoms selected from O, S, N, and P, C₃ to C₈ heteroaryl with from 1 to 3 heteroatoms selected from O, S, N, and P, or combinations thereof. In an embodiment, one or more R_y can be connected to form a single ligand, but with two carboxylate binding sites, such as in Formula X-B.

[0045] In an embodiment, the Rh catalyst is represented by the compound of

Formula X-B, Rh₂(esp)₂.

[0046] In an embodiment, the Rh catalyst is represented by the compound of Formula X-

C, wherein each is a C₅ to C₈ aryl, optionally substituted with from 1 to 3 halogen

atoms or a C₅ to C₈ heteroaryl with from one to 1 heteroatoms selected from N, O, or S, optionally substituted with from 1 to 3 halogen atoms.

[0047] In an embodiment, the Rh catalyzed cyclopropanation reaction comprises from about 0.0001 mol% to about 1 mol%, from about 0.0001 to about 0.1 mol%, from about 0.001 to about 0.01 mol%, or about 0.005 mol% of the Rh catalyst.

[0048] The mol% of the Rh catalyst can be based on the amount of the diazo compound and/or the cyclic compound in moles. The mol % of the Rh catalyst can be based on a mathematical percentage of moles of either the amount of the diazo compound and/or the cyclic compound.

[0049] The Rh catalyzed cyclopropanation reaction can proceed in a suitable nonpolar aprotic solvent, such as toluene, dichloromethane, and/or dimethyl carbonate.

[0050] In an embodiment, the Rh catalyzed cyclopropanation reaction can be performed at from about 0 °C to about 100 °C, from about 25 °C to about 95 °C, or from about 70 °C to about 90 °C.

[0051] In an embodiment, the Rh catalyzed cyclopropanation reaction can result in the intermediate compound of Formula XI, wherein A can be H or an organic protecting group and X can be OH, O-R_x, NH₂, or a halogen, and R_x can be C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens.

Formula XL Intermediate Compound.

[0052] The intermediate compound of Formula XI can be a mixture of the exo stereoisomer, wherein the carbonyl functional group is in the same orientation as the hydrogen atoms, and the endo stereoisomer, wherein the carbonyl functional group is in the opposite orientation as the hydrogen atoms, as shown in Formula XII.

Formula XII. Exo (left) and Endo (right) stereoisomers that can be generated as a result of the Rh catalyzed cyclopropanation reaction described herein.

[0053] Disclosed herein is a method to generate a stereochemically pure composition including either the exo stereoisomer or the endo stereoisomer from a composition including both the exo and endo stereoisomer through an epimerization and/or hydrolysis reaction under basic conditions.

[0054] In an embodiment, the exo stereoisomer can be isolated from a composition comprising a mixture of the exo and endo stereoisomers by adding the intermediate compound of Formula XI to a polar aprotic solvent, such as THF, and adding from 1 to 5 equivalents, preferably 3 equivalents, of a strong base, such as sodiumtert-butoxide, potassium tert-butoxide, sodium ethoxide, 1,8-Diazabicyclo [5.4.0]undec- 7-ene (DBU), triazabicyclodecene (TBD), or 2-tert-Buty1-1,1,3,3-tetramethylguanidine (BTMG). While not wishing to being bound by theory, it is believed that the exo stereoisomer is the more thermodynamically stable stereoisomer, thus, the addition of a strong base can result in the isomerization of the endo stereoisomer to the exo stereoisomer. If the resulting exo stereoisomer is in the form of an ester (z.e. if X is OR_x and R_x is C₂ alkyl), the isomerization reaction can be followed by the addition of a base, such as NaOH to hydrolyze the ester to a carboxylic acid or a salt thereof. The exo stereoisomer of Formula XII can be isolated through extraction.

[0055] In an embodiment, the stereochemically pure composition comprising the exo stereoisomer can have at least about 15:1, at least about 20:1, at least about 25:1, at least about 30 : 1 , or greater than 30:1 d.r . (ratio of exo to endo stereoisomer) . [0056] In an embodiment, the endo stereoisomer can be isolated from a composition comprising a mixture of the exo and endo stereoisomers through a selective hydrolysis reaction in a polar protic solventf, and an aqueous base, such as NaOH. The endo stereoisomer can be isolated through extraction with a nonpolar solvent, such as n- hexane, during the selective hydrolysis reaction. The endo ester can be further converted to the endo acid by exposing the endo ester to a prolonged exposure in polar protic solvent, such as aqueous ethanol or pure ethanol, and an aqueous base, such as NaOH.

[0057] In an embodiment, the polar protic solvent can comprise ethanol, methanol, isopropanol, or combinations thereof. In an embodiment, the polar protic solvent can comprise aqueous ethanol, aqueous methanol, aqueous isopropanol, or combinations thereof.

[0058] In an embodiment, the Rh catalyst from Formula X-C can be used to generate a composition that is enriched in endo stereoisomer. This can allow for the selective hydrolysis of the remaining exo stereoisomer at the same time as the enriched endo stereoisomer is extracted. Suitable compositions can have a ratio at least 2:1, at least 3:1, or at least 4:1 endo.exo stereoisomers of the intermediate compound ofFormula XII.

[0059] In an embodiment, the stereochemically pure composition comprising the endo stereoisomer can have at least about 1:15, at least about 1:20, at least about 1:25, at least about 1:30, or greater than 1:30 d.r. (ratio of exo to endo stereoisomer).

Step (ii) - Amide Coupling Reaction

[0060] Step (ii) of the method to prepare a SSTR4 agonist compound can include the mixing the intermediate compound generated in step (i), such as the intermediate compound ofFormula XI or a composition comprising a stereochemically pure exo or endo stereoisomer shown in Formula XII, with a suitable as shown in Formula XIII.

Formula XIII. Step (ii) of Method for Preparing SSTR4 Agonist [0061] Step (ii) of the method to prepare a SSTR4 agonist compound can also include the mixing the intermediate compound generated in step (i), (1R,5S)-3-(A)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid, with 2-( 1-methyl-1H-indazo1-3-y l)propan-2- amine, as shown in Formula XIV.

Formula XIV. Step (ii) of Method for Preparing SSTR4 Agonist

[0062] Step (ii) of the method to prepare a SSTR4 agonist compound can include the mixing the intermediate compound generated in step (i), (1R,5S)-3-(A)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid, with 2-Methyl-1-((3-methylpyridin-2- yl)oxy)propan-2 -amine as shown in Formula XV.

Formula XV. Step (ii) of Method for Preparing SSTR4 Agonist

[0063] Prior to the addition of the suitable amine, the intermediate compound can be reacted with a suitable reagent, such as oxalyl chloride or thionyl chloride, to generate an acid chloride in situ, replacing the -OH functional group with a -Cl under synthetic conditions well known to a person of ordinary skill in the art.

[0064] The generated acid chloride can be combined with a suitable amine at a temperature of from about -10 °C to about 10 °C or from about 0 °C to about 10 °C.

[0065] The solution temperature can be increased to from about 15 °C to about 25 °C after from about 2 to about 4 hrs.

[0066] Some examples of suitable amines include 2-methyl -1-((3-methylpyridin- 2-yl)oxy)propan-2-amine, 2-(1-methyl-1H-indazo1-3-yl)propan-2-amine, among others. Suitable amines can be selected to yield the desired SSTR4 agonist compound. [0067] In another embodiment, step (ii) can comprise mixing intermediate

[0068] In another embodiment, step (ii) can comprise mixing intermediate

[0069] In another embodiment, step (ii) can comprise mixing intermediate

Step (iii) - Removal of Organic Protecting Group (A)

[0070] In some embodiments, if A was an organic protecting group in steps (i) and/or (ii), the organic protecting group can be removed to yield the SSTR4 agonist compound. A person of ordinary skill in the art would understand how to remove an organic protecting group from an amine, as disclosed.

[0071] Step (iii) of the method to prepare a SSTR4 agonist compound can include the mixing the product generated in step (ii), such as ((1R,5S,6r)-N-(2-Methyl-1-((3- methylpyridin-2-yl)oxy)propan-2-yl)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carboxamide, with potassium diphenylphosphine as shown in Formula XVI.

Formula XVI. Step (iii) of Method for Preparing SSTR4 Agonist [0072] ((1R,5S,6r)-N-(2-Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-A- 3-azabicyclo[3.1.0]hexane-6-carboxamide can be dissolved in a suitable solvent, such as methyl tert-butyl ether. The temperature can be decreased to from about -100 °C to about -50 °C, from about -80 °C to about -55 °C, or from about -70 °C to about -60 °C. Potassium diphenylphosphine can be added dropwise with the decreased temperature maintained.

[0073] After the entire amount of potassium diphenylphosphine has been added, the solution decreased temperature can be maintained for at least 4 hrs., at least 6 hrs., or at least 8 hrs. The solution can then be allowed to rise to a temperature of from about 15 °C to about 25 ⁰ C and the SSTR agonist compound, (lS,5R)-N-[1,1-Dimethyl-2-[(3- methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide can be isolated from solution using typical methods well known to a person of ordinary skill in the art.

[0074] In another embodiment, step (iii) can comprise mixing

potassium diphenylphosphide to yield the

SSTR4 agonist compound.

Intermediate Compound

[0075] Also disclosed herein are novel intermediate compounds generated during the disclosed method for the preparation of the SSTR4 agonist compounds or salts thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and/or solvates thereof. Suitable intermediates can be generated at any time during the disclosed method. Suitable intermediates can be isolated as a neat compound or generated only in solution.

[0076] Suitable intermediates for the preparation of SSTR4 agonist compounds or salts thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and/or solvates thereof, can include the intermediates of Formula XI, Formula XII, salts thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and/or solvates thereof, wherein A is H or an organic protecting group, such as /ert-butyloxycarbonyl (Boc), tosyl (Tos), carbobenzyloxy (Cbz), or fluorenylmethyloxycarbonyl (Fmoc), X can be OH, O- R_x, NH₂, NH-R_x,N(RX)₂ or a halogen, and R_x can be C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens.

[0077] In some embodiments, the intermediate compound can be presented by Formula XVII, wherein A can be H or an organic protecting group and R_x can be C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens.

Formula XVII. Intermediate Compounds.

[0078] The intermediate compound, as described herein, can be used for the preparation of the SSTR4 agonist compound or pharmaceutically acceptable salts thereof, hydrates thereof, and/or solvates thereof. The intermediate compound offers a stable scaffold to produce a variety of SSTR4 agonist compounds through an amide-carboxylic acid coupling reaction, such as in step (ii) of the method for preparing the SSTR4 agonist compound, as described herein and illustrated in Formula VIII.

[0079] TABLE 1 displays some possible SSTR4 agonist compounds that can be synthesized using the disclosed method through the intermediate compound. Even though TABLE 1 only shows the exo stereoisomer of the intermediate compound, the endo stereoisomer could also have been selected. TABLE 1. SSTR4 Agonist Compounds that Can be Synthesized Using Amide Coupling

Reaction with Intermediate Compound

Chiral Catalysts

[0080] The chiral catalysts in Table 2 were used in this study.

TABLE 2.

Preparations

Preparation for (1R,5S,6r)-3-(tert-Butoxycarbonyl)-3-azabicyclo[3.L0]hexane-6- carboxylic acid

Step 1

3-(tert-Butyl) δ-ethyl (1R,5S)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (Exolendo)

[0081] To a flame-dried 50 mL flask charged with an octagonal stir-bar (1 in x 5/16 in) stir-bar and 10 g of activated 4Å molecular sieves was added tert-butyl 2,5- dihydro-1H-pyrrole-1 -carboxylate (3.384 g, 20.00 mmol). The reactor was backfilled with nitrogen three times and then capped with a nitrogen balloon. Then dimethyl carbonate (17.57 mL) was added followed by a solution of Rh(II)₂(esp)₂ in CH₂CI₂ (379.2 pg, 1.00 mL, 0.500 μmol). The reaction was then stirred at 300 rpm at a temperature of 90 °C for 10 min. After the elapsed time, a solution of ethyl 2-diazoacetate in DCM (1.542 g, 1.421 mL, 10.00 mmol) was added via a dua1-syringe pump [dua1-syringe pump settings — 3 mL syringe, 0.475 mL/hr., diameter 9.83 mm, vol 1.425 mL; Air- Tite™/SilverPoint 22Gx4" long hypodermic needle was used] over 3 hrs., keeping the tip of the needle submerged into the reaction solution. Then, the reaction mixture was stirred at 90 °C for an additional 2.5 hrs. The reaction was cooled down to ambient temperature, filtered over a plug of diatomaceous earth, and the filtrate concentrated in vacuo at 50 °C. The straw-colored crude material was subjected to a Kugelrohr distillation to separate products from excess of starting material. The starting material distilled at 110 °C at 5 to 6 x10-1 torr and the product at 170 °C at 5 - 6 x 10-1 torr. The distillate was collected to give 3 -(tert-butyl) δ-ethyl {1R, 5S)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate {exo/endo) (2.30 g, 90.1%, exotendo 49:51) as a straw-colored oil.

[0082] ¹H NMR (CDCl₃) δ [49:51 mixture of exo:endo] 4.15 - 4.07 {exo/endo m, 4.7H), 3.80 - 3.72 {endo dd, J = 21.9, 11.1 Hz, 2.1H), 3.69 - 3.58 {exo dd, J = 32.4, 11.2 Hz, 2H), 3.45 - 3.38 {exo/endo dtd, J = 11.1, 7.9, 7.5, 4.1 Hz, 4.1H), 2.07 - 2.05 {exo m, 2H), 1.89 - 1.83 {endo ddd, J = 7.7, 3.3, 1.4 Hz, 2.1H), 1.78 - 1.74 {endo dd, J = 8.8, 7.3 Hz, 1.0H), 1.49 {exo d, J = 2.7 Hz, 0.9H), 1.43 {exo s, 8.7H), 1.42 {endo s, 9.3H), 1.25 {exo/endo td, J = 7.2, 2.9 Hz, 7.2H).

[0083] HRMS (+p ESI): calc, mass for C₁₃H₂₂O₄N [M + H]+ - 256.15433; obs. mass for C₁₃H₂₂O₄N [M + H]+ - 256.15409.

Step 2

3-(tert-Butyl) δ-ethyl (1R,5S,6s)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate

[0084] To a 4 mL vial charged with a stir-bar was added 3 -(tert-butyl) δ-ethyl (1R,5S)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate {exo/endo) (128 mg, 0.500 mmol, exo. endo 49:51), ethanol (500 μL), and IM sodium hydroxide in deionized water (20.0 mg, 500 μL). The reaction was capped and stirred at 25 °C for 120 min. After the elapsed time, the reaction mixture was extracted with hexanes three times, the organic layer dried with MgSO₄, filtered, and the filtrate concentrated in vacuo at 45 °C to give 3-(tert-butyl) 6-ethyl (1R,5S',6s)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate {endo) (47.4 mg, 37.1%, 72% recovered yield, exo'.endo d.r. <1:30) as a clear non-colored oil. [0085] ¹H NMR (CDCl₃) δ 4.11 - 4.05 (m, 2H), 3.78 - 3.70 (dd, J = 21.4, 11.1

Hz, 2H), 3.44 - 3.37 (ddd, J = 13.2, 7.8, 2.7 Hz, 2H), 1.87 - 1.81 (m, 2H), 1.78 - 1.73 (m, 1H), 1.41 (s, 9H), 1.25 - 1.22 (t, J = 7.1 Hz, 3H).

[0086] ¹³C NMR (CDCl₃) δ 168.9, 154.0, 79.3, 60.5, 45.6, 45.4, 28.4, 22.3, 21.8,

21.2, 14.2.

[0087] HRMS (+p ESI): calc, mass for C₁₃H₂₂O₄N [M + H]+ - 256.15433; obs. mass for C₁₃H₂₂O₄N [M + H]+ - 256.15384.

Step 3

(1R,5S,6s)-3-(tert-Butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[0088] A 20 mL vial was charged with a stir-bar and 3 -(tert-butyl) δ-ethyl (1R,5S',6s)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (128 mg, 0.500 mmol, exo'.endo d.r. <1:30) was added ethanol (2.50 mL) and 2M sodium hydroxide in deionized water (200 mg, 2.50 mL) and then capped. The reaction solution was stirred vigorously at ambient temperature for 24 hrs. After the elapsed time, the mixture was washed with hexanes three times and then the aqueous solution was concentrated in vacuo at 45 °C. The concentrated aqueous solution was cooled with a saltwater ice bath and slowly acidified with IM HCl to a pH of 1-2. Then, the aqueous solution was extracted with ethyl acetate three times, the organic layer dried with MgSO₄ , filtered, and the filtrate was concentrated in vacuo at 50 °C to give (1R,5S,6s)-3-(tert-butoxycarbonyl)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid (101 mg, 88.9%, exo'.endo d.r. <1:30) as a white solid.

[0089] ¹H NMR (CDCl₃) δ 3.76 - 3.73 (d, J = 11.4 Hz, 2H), 3.52 - 3.48 (dt, J = 11.4, 2.2 Hz, 2H), 2.0 - 1.94 (ddd, J = 8.1, 3.0, 1.4 Hz, 2H), 1.80 - 1.76 (t, J = 8.1 Hz, 1H), 1.43 (s, 9H).

[0090] ¹³C NMR (CDCl₃) δ 174.5, 154.3, 79.5, 45.6, 28.5, 23.2, 22.5.

[0091] HRMS (-p APCI): calc, mass for C₁₁H₁₆O₄N [M - H]- - 226.10848; obs. mass for C₁₁H₁₆O₄N [M - H]- - 226.10854. Step 4

(1R,5S,6r)-3-(terZ-Butoxycarbonyl)-3-azabicyclo[3.1 ,0]hexane-6-carboxylic acid

[0092] A round-bottom flask provided with a stir-bar was charged with 3 -(tert- butyl) δ-ethyl (1R,5S)-3-azabicyclo[3. l ,0]hexane-3,6-dicarboxylate (exo/endo) (128 mg, 0.500 mmol, exo.endo d.r. ~1:1) and 2 M sodium tert-butoxide in THF (750 μL). The reaction mixture was allowed to stir at ambient temperature for 10 min prior to the addition of ethanol (2.50 mL) and 2 M sodium hydroxide in deionized water (2.50 mL). After stirring at 25 °C for 24 hrs., the mixture was concentrated in vacuo at 45 °C and the aqueous solution was washed with diethyl ether five times. The aqueous solution was cooled with a saltwater ice bath and slowly acidified with IM HCl to a pH of 1-2. Subsequently, the aqueous solution was extracted with ethyl acetate three times and the organic layer dried with MgSO₄, filtered, and concentrated in vacuo at 50 °C to give a crude mixture as a brown oil. This oil was triturated while sonicating in n-heptane, filtered, and the filter cake dried under vacuum to give (1R,5S,6r)-3-(tert- butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (exo) (98 mg, 86%; over 2 steps, exo:endo d.r. >30:1) as a pale orange powder.

[0093] ¹H NMR (CDCI₃) δ 3.71 - 3.68 (d, J = 1 1.3 Hz, 1H), 3.63 - 3.60 (d, J = 1 1.3 Hz, 1H), 3.45 - 3.40 (td, J = 8.3, 4.2 Hz, 2H), 2.13 - 2.12 (d, J = 2.6 Hz, 2H), 1 .49 - 1.48 (t, J = 3.0 Hz, 1H), 1.43 (s, 9H).

[0094] ¹³C NMR (CDCl₃) δ 178.3, 154.7, 80.0, 47.9, 47.6, 28.4, 27.3, 26.6, 24.2.

[0095] HRMS (-p APCI): calc, mass for C₁₁H₁₆O₄N [M - H]- - 226.10848; obs. mass for C₁₁H₁₆O₄N [M - H]- - 226.10847.

Preparation for (1R,5S',6r)-3-(p-toluensulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

Step 1 - "one-pot” synthesis of exo-3-(p- toluensulfonyl)-3-azabicyclo[3.1.0]hexane-6- carboxylic acid

[0096] A flame-dried 50 mL round-botom flask provided with a stir-bar was charged with 10 g of activated 4 A MS and 1-tosy1-2,5-dihydro-1H-pyrrole (4.5 g, 20 mmol, 2.0 equiv.). The reactor was backfilled with nitrogen three times and then capped with a nitrogen balloon. Then, dimethyl carbonate (17.6 mL) was added followed by a stock solution of Rh(II)₂ (esp)₂ in CH₂CI₂ (379.2 pg, 1.000 mL, 0.00050 molar, .00005 equiv, 0.5000 pmol). The reaction was then stirred at 300 rpm at 90 oC for 10 min. before the addition of a solution of ethyl 2-diazoacetate in CH₂ CI₂ (1.542 g, 1.421 mL, 74% Wt, 10.00 mmol, 1 equiv.) via a dua1-syringe pump [dua1-syringe pump setings, 3 mL syringe, 0.475 mL/hr, diameter 9.8 mm, vol 1.425 mL; Air-Tite/Silverpoint 22Gx4" long hypodermic needle was used] over 3 h. The resulting solution was reacted for an additional 2.5 h and then cooled to room temperature, filtered over a plug of celite, and the filtrate concentrated in a rotavapor at 50 °C (bath temperature). The residue was then treated with a 2 M solution of sodium tert-butoxide in THF (15 mL, 30 mmol), upon which an immediate color change to brown-orange was observed. The reaction mixture was allowed to stir 10 minutes at room temperature to ensure complete isomerization before adding ethanol (49.9 mL) followed by 2 M solution of sodium hydroxide in deionized water (50 mL). Then, the reaction mixture was allowed to stir at 25 °C for 46 h, the solids were filtered through a fritted funnel rinsing the filter cake with deionized water, and the resulting orange filtrate was concentrated in the rotavapor at 55 °C (bath temperature) to a basic aqueous suspension (pH 14). The suspension was diluted with deionized water and heated to 75 °C in a water bath for 10 min. The hot suspension was then vacuum filtered through a fritted funnel rinsing the solids with warm deionized water resulting in a yellow filtrate. The combined filter-cakes resulted in a 2.88 g (0.71 equiv.) of recovered clean starting material (1-tosy1-2,5-dihydro-1H-pyrrole) as a white powder. The basic yellow filtrate was placed into a saltwater ice bath, cooled, and slowly acidified with IM HCl aqueous solution until pH 1 resulting in a white cloudy suspension. The aqueous suspension was extracted with ethyl acetate five times, the organic layer dried over anhydrous MgSO₄, filtered through celite, and the filtrate concentrated in the rotavapor at 55 °C (bath temperature) resulting in an off-white solid. The solid was resuspended in n-heptane, sonicated, and the suspension was filtered using a fine porosity filter paper and a funnel. The filtered cake was washed with n-heptane, triturated, and dried under vacuum to afford (1R,5S,6r)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (exo) (1.6 g, 5.8 mmol, 58.1 % yield over 3 steps, exo'.endo d.r. >30:1) as a light tan fluffy powder.

[0097] ¹H NMR (CDCl₃) δ 7.68 - 7.66 (d, J = 8.3 Hz, 2H), 7.35 - 7.33 (d, J = 7.7

Hz, 2H), 3.64 - 3.61 (d, J = 9.8 Hz, 2H), 3.15 - 3.09 (d, J = 9.6 Hz, 2H), 2.44 (s, 3H), 2.06 - 2.02 (m, 2H), 1.71 - 1.69 (t, J = 3.0 Hz, 1H).

[0098] ¹³C NMR (CDCl₃) δ 177.8, 143.9, 133.0, 129.8, 127.6, 49.3, 26.4, 22.4,

21.6.

[0099] HRMS (-p APCI): calc, mass for C₁₃H₁₄O₄N³²S [M - H]- 280.0649; obs. mass for C₁₃H₁₄O₄N³²S [M- H]- - 280.06453.

Preparation 2

Step 1

1 ,2-bis(3,5-Dibromophenyl)ethane- 1 ,2-dione

[0100] This compound was made from a modified procedure from Dhayalan, V.; Gadekar, S. C.; Alassad, Z.; Milo, A. Unravelling mechanistic features of organocatalysis with in situ modifications at the secondary sphere. Nature Chemistry 2019, 11 (6), 543- 551. To a flame-dried flask charged with a stir-bar was added 2-(perfluorophenyl)-6,7- dihydro-5H-pyrrolo[2,1-c][l,2,4]triazo1-2-ium tetrafluoroborate (2.90 g, 8.00 mmol) (synthesized via OrgSyn procedure (Org. Synth. 2010, 87, 350) and potassium carbonate (1.11 g, 8.00 mmol) in THF (200 mL, 200 mmol). The mixture was stirred for at least 5 minutes at ambient temperature. To the reaction mixture was added 3,5- dibromobenzaldehyde (52.8 g, 200 mmol). The solution was stirred for 24 hrs., at ambient temperature. After the elapsed time, the reaction was concentrated in vacuo at 40 °C. The benzoin crude was subjected to the next step as a crude orange residue.

[0101] To a IL flask charged with a stir-bar was added the crude benzoin, ammonium nitrate (20.0 g, 250 mmol), and copper(II) acetate monohydrate (5.03 g, 25.2 mmol). Subsequently, acetic acid (800 mL) was added to the vessel. The reaction vessel was then equipped with a Findenser™ and was stirred at 130 °C for 24 hrs., open to air. After the elapsed time, ice was added to the reaction vessel to aid in the cooling of the reaction solution and precipitation of product. Enough ice was added to the mixture until the reaction solution cooled and ice seen floating atop the reaction solution. This resulted in a green-yellow suspension. The precipitate was vacuum filtered through a fritted funnel, washed with excess deionized water and then excess ice/ethanol mixture until the filtrate ran clear and colorless. Ambient temperature ethanol was used to further wash the filter cake until eluent ran clear and colorless. The bright yellow filter cake was vacuum dried to give l,2-bis(3,5-dibromophenyl)ethane- 1,2-dione (43 g, 41%) as a bright yellow powder.

[0102] ¹H NMR (CDCl₃) δ 8.03 - 8.02 (d, J = 1.8 Hz, 4H), 7.98 - 7.97 (t, J = 1.8 Hz, 2H).

[0103] ¹³C NMR (CDCl₃) δ 189.4, 140.4, 135.1, 131.6, 124.0.

[0104] HRMS (+p APCI): calc, mass for C₁₄H₇O₂ ⁷⁹Br₄ [M+H]+ - 522.71741; obs. mass for C₁₄H₇O₂ ⁷⁹Br₄ [M+H]+ - 522.71761.

Step 2

1 ,3 -b is(3 , 5 -Dibromophenyl)propan-2-one

[0105] To a 2L flask charged with a stir-bar was added l,3-dibromo-5- (bromomethyl)benzene (23 g, 70 mmol), tetrabutylammonium bromide (4.5 g, 14 mmol), tosylmethyl isocyanide (6.8 g, 35 mmol), and DCM (3.0 g, 0.70 L, 35 mmol). The reaction mixture was allowed to stir and subsequently, sodium hydroxide in deionized water (64 g, 0.32 L, 1.6 mol) was added to the mixture. The reaction mixture was allowed to stir for 24 hrs., at 25 °C open to air. After the elapsed time, deionized water was poured into the reaction solution and allowed to stir for 5 minutes. The aqueous layer was decanted. This wash technique was repeated three times. Afterwards, the organic layer was concentrated via a stream of air.

[0106] Once the crude material had dried, DCM (233 mL), THF (46 mL), and concentrated 12M HCl (23 mL) was added to the crude material. The mixture was allowed to stir at ambient temperature for 20 hrs. The reaction mixture was then neutralized with saturated bicarbonate solution while the solution stirred. Subsequently, a stream of air was placed in the vessel to evaporate the organic solvents, leaving just the aqueous suspension. The suspension was filtered, the filter cake washed with deionized water, and then triturated with excess ethanol to give a white filter cake. The white filter cake was vacuum dried to give l,3-bis(3,5-dibromophenyl)propan-2-one (15.95 g, 87%) as a white powder.

[0107] ¹H NMR (CDCl₃) δ 7.60 - 7.59 (t, J = 1.8 Hz, 2H), 7.24 - 7.23 (d, J = 1.7

Hz, 4H), 3.69 (s, 4H).

[0108] ¹³C NMR (CDCl₃) δ 202.4, 136.9, 133.1, 131.3, 123.2, 48.3.

[0109] HRMS (+p APCI): calc, mass for C₁₅H₁₁O⁷⁹Br4 [M + H]+ - 522.75379; obs. mass for C₁₅H₁₁O⁷⁹Br4 [M + H]+ - 522.75292.

Step 3

2,3,4,5-tetrakis(3,5-Dibromophenyl)cyclopenta-2,4-dien-1-one

[0110] To a flask charged with a stir-bar was added l,2-bis(3,5- dibromophenyl)ethane- 1,2-dione (10.62 g, 20.20 mmol), tetrabutylammonium bromide (716.3 mg, 2.222 mmol), and l,3-bis(3,5-dibromophenyl)propan-2-one (10.62 g, 20.20 mmol) in toluene (166 mL) and deionized water (11.9 mL). The reaction mixture was heated to 95 °C while stirring open to air. Once the temperature was reached, pellets of potassium hydroxide (1.667 g, 85% wt, 25.25 mmol) was slowly added to the mixture. The resulting solution turned from a dark yellow suspension to a dark-red homogenous solution. The reaction was allowed to stir at 95 °C for 2 hrs. After the elapsed time, the resulting mixture was concentrated in vacuo at 80 °C to give a purple amorphous solid. The dried purple amorphous solid was resuspended in ethanol, sonicated, and then filtered and washed with excess ethanol to give 2,3,4,5-tetrakis(3,5-dibromophenyl)cyclopenta- 2,4-dien-1-one (13.28 g, 64.73%) as a purple powder.

[0111] ¹H NMR (CDCl₃) δ 7.71 - 7.70 (t, J = 1.8 Hz, 2H), 7.63 - 7.62 (t, J = 1.8 Hz, 2H), 7.30 (d, J = 1.7 Hz, 4H), 7.00 (d, J = 1.8 Hz, 4H). [0112] ¹³C NMR (CDCl₃) δ 196.6, 152.1, 135.4, 134.4, 134.2, 132.2, 131.4,

130.5, 124.2, 123.3, 122.9.

[0113] HRMS (+p APCI): calc, mass for C₂₉H₁₃O⁷⁹Br₈ [M + H]+ - 1008.44279; obs. mass for C₂₉H₁₃O⁷⁹Br₈ [M + H]+ - 1008.44393.

Step 4

4,5,6,7-tetrakis(3,5-Dibrornophenyl)isobenzofuran-1,3-dione

[0114] To a flame-dried flask charged with a stir-bar was added 2, 3, 4, 5- tetrakis(3,5-dibromophenyl)cyclopenta-2,4-dien-1-one (12.19 g, 12.00 mmol), maleic anhydride (2.353 g, 24.00 mmol), and bromobenzene (48.00 mL). The reaction vessel was equipped with a Findenser™ and the purple suspension was heated to 175 °C while stirring for 18 hrs. After the elapsed time, the reaction solution is brown-purple suspension. A stream of air was blown into the reaction vessel to cool the solution to ambient temperature, which resulted in a brown-purple suspension. Then bromine (4.794 g, 1.546 mL, 30.00 mmol) was added drop-wise into the reaction vessel. The vessel was heated to 65 °C for 24 hrs., with an outlet-tube connected to the top of the Findenser™ into a beaker of IM sodium thiosulfate solution. After the elapsed time, the reaction solution was allowed to cool to ambient temperature by blowing a stream of air which resulted in a light brown suspension. The reaction solution was then quenched with IM sodium thiosulfate solution. To this suspension was diluted with deionized water. To the aqueous solution was diluted with ethyl acetate and extracted with ethyl acetate three times. The organic layer was dried with MgSO₄, filtered, and the filtrate concentrated in vacuo at 70 °C to give a purple-red solid. The purple-red solid was resuspended in diethyl ether, sonicated, and filtered through a fritted funnel under vacuum. The filter cake was collected and vacuum dried to give 4,5,6,7-tetrakis(3,5-dibromophenyl)isobenzofuran- 1, 3-dione (4.7 g, 36%) as a cream solid.

[0115] ¹H NMR (CDCl₃) δ 7.66 - 7.65 (t, J = 1.7 Hz, 2H), 7.45 - 7.44 (t, J = 1.7 Hz, 2H), 7.21 - 7.20 (d, J = 1.7 Hz, 4H), 6.93 (d, J = 1.7 Hz, 4H).

[0116] ¹³C NMR (CDCl₃) δ 160.1, 146.9, 138.6, 138.5, 135.9, 134.6, 133.9,

131.6, 131.0, 128.6, 122.8, 122.7.

[0117] HRMS (+p APCI): calc, mass for C₃₂H₁₃O₃ ⁷⁹Br8 [M + H]+ - 1076.43262; obs. mass for C₃₂H₁₃O₃ ⁷⁹Br₈ [M + H]+ - 1076.43384.

Step 5

(S)-3,3-Dimethyl-2-(4,5,6,7-tetrakis(3,5-dibromophenyl)-1,3-dioxoisoindolin-2- yl)butanoic acid

[0118] To a flame-dried flask charged with a stir-bar was added 4, 5,6,7- tetrakis(3,5-dibromophenyl)isobenzofuran- 1,3-dione (2.17 g, 2.00 mmol), 3-methyl -L- valin (L-tert-Leucine) (315 mg, 2.40 mmol), and toluene (184 mg, 20.0 mL, 0.1 molar, 2.00 mmol). Subsequently, triethylamine (263 mg, 362 μL, 2.60 mmol) was added to the solution. The resulting solution was a brown suspension. The reaction vessel was equipped with a Findenser™ open to air and the reaction suspension was heated to 120 °C for 24 hrs. The reaction solution was concentrated in vacuo at 50 °C, the dried material diluted with IM HCl solution, sonicated vigorously, and then diluted with ethyl acetate. The organic layer was then extracted with ethyl acetate three times, the organic layers combined and dried with MgSC>4, filtered, and the filtrate concentrated in vacuo at 40 °C. The crude material was dry-1oaded on SiO₂ and subjected to SiO₂ flash chromatography eluting with hexanes in ether solvent system (50 g Biotage® DLV Sfar column; 0% ether for 3CV; 0 to 25% ether for 3CV ; 25% ether for 3CV; 25 to 75% ether for 3CV; 75% ether for 3CV; 75% to 100% ether for 3CV; 100% ether for 5CV; 100 mL/min flow-rate; 210/254 nm detector; product elutes at 25% ether). The collected fractions were concentrated in vacuo to give (5)-3,3-dimethyl -2-(4,5,6,7-tetrakis(3,5- dibromophenyl)-1,3-dioxoisoindolin-2-yl)butanoic acid (1.88 g, , 78.5%) as a cream powder.

[0119] ¹H NMR (CDCl₃) δ 7.61 - 7.60 (t, J = 1.7 Hz, 2H), 7.41 - 7.40 (t, J = 1.7 Hz, 2H), 7.25 (s, 2H), 7.15 (s, 2H), 6.92 - 6.91 (d, J = 1.7 Hz, 4H), 4.67 (s, 1H), 1.15 (s, 9H).

[0120] ¹³C NMR (CDCl₃) δ 165.5, 145.1, 139.2, 137.1, 136.9, 134.0, 133.5,

131.8, 131.8, 131.3, 131.2, 128.6, 122.4, 122.4, 60.1, 35.7, 28.0.

[0121] HRMS (+p APCI): calc, mass for C₃₈H₂₄O₄N⁷⁹Br₈ [M + H]+ - 1 189.51669; obs. mass for C₃₈H₂₄O₄N⁷⁹Br₈ [M + H]+ - 1189.51885.

Step 6

[0122] To a flame-dried flask charged with a stir-bar was added diacetoxyrhodium (80 mg, 0.18 mmol), (5)-3,3-dimethyl-2-(4,5,6,7-tetrakis(3,5- dibromophenyl)-1,3-dioxoisoindolin-2-yl)butanoic acid (1.7 g, 1.4 mmol), and chlorobenzene (20 mg, 18 mL, 0.01M, 0.18 mmol). The vessel was equipped with a Soxhlet apparatus charged with potassium carbonate and topped with a Findenser™ and nitrogen balloon. The mixture was vigorously stirred and heated to 175 °C for 65 hrs. The chlorobenzene was distilled off and then the crude solid was dry-1oaded onto SiO₂ as a fine-green powder and subjected to SiO₂ flash chromatography (hexanes/ether solvent system; 25 g Biotage® DLV Sfar column; 0% ether for 5CV; 0 to 5% ether for 5CV; 5% ether for 5CV; 5% to 10% ether 5CV; 10% ether for 5 CV; 100 mL/min flow-rate; 210/254 nm detector; product elutes at 5% ether). The collected fractions were concentrated in vacuo at 60 °C to give Rh₂[S-tetra-(3,5-di-Br)TPPTTL]4 (350 mg, 39%) as a green powder.

[0123] Crystallization - The solids were dissolved in CDCl₃, the solution placed into a culture tube, the solution was layered with benzene on top. The culture tube was placed into a scintillation tube and allowed to crystallize out through slow evaporation. Crystals became apparent within a couple of hours.

[0124] ¹H NMR (CDC₁₃ ) δ 7.66 - 7.65 (t, J = 1.8 Hz, 1H), 7.41 - 7.37 (m, 4H), 7.24 - 7.23 (t, J = 1.7 Hz, 1H), 7.04 - 7.03 (d, J = 1.6 Hz, 1H), 6.96 - 6.93 (dt, J = 9.2, 1.6 Hz, 2H), 6.80 (s, 1H), 6.75 - 6.74 (t, J = 1.6 Hz, 1H), 6.61 - 6.60 (t, J = 1.6 Hz, 1H), 3.83 (s, 1H), 0.77 (s, 9H).

[0125] ¹³C NMR (CDC₁₃ ) δ 186.6, 164.9, 164.5, 144.8, 144.4, 139.6, 139.6,

137.7, 136.9, 136.5, 136.3, 133.8, 133.7, 133.3, 132.4, 132.0, 131.7, 131.3, 131.2, 129.0, 128.9, 123.0, 122.4, 122.4, 122.4, 122.3, 122.2, 122.0, 121.6, 35.8, 29.7, 27.7.

[0126] HRMS (+p ESI): calc, mass for C₁₅₂H₈₉O₁₆N4⁷⁹Br₂₄ ⁸¹Br8¹⁰³Rh₂ [M + H]+ - 4972.80825; obs. mass for C₁₅₂H₈₉O₁₆N4⁷⁹Br₂₄ ⁸¹Br₈ ¹⁰³Rh₂ [M + H]+ - 4972.82459

Examples

Example 1 - Determination of suitable of Rh(II) Catalysts

Scheme 2

[0127] A study for the cyclopropanation of N-Boc-2,5-dihydropyrrole (Ambeed, TCI Chemicals, Combi-Blocks), was developed to screen for suitable Rh catalysts. The cyclopropanation of dihydropyrrole was conducted with ethyl diazoacetate (Sigma- Aldrich) and summarized in Table 3. All of these reactions were conducted with an excess of trapping agent to promote effective trapping of the Rh carbene and mitigate catalyst degradation. With a catalyst loading of 1 mol % all the catalysts performed well giving the intermediate compound in reasonable yield but with low levels of diastereo- control.

TABLE 3.

[0128] The catalyst screening on Table 3 was performed at 0.500 mmol scale. Temperature was recorded via heat-block and not internal temperature of reaction. Diastereomeric ratio (exo.endo d.r.) was calculated from crude ¹HNMR by integrating broad multiplet at 2.10 - 2.02 ppm (exo 2H) & multiplet 1.89 - 1.82 ppm (endo 2H). 1HNMR yield was calculated by quantitative 1HNMR analysis with 1,3,5- trimethoxybenzene as an internal standard by integrating 6.01 ppm (3H) and product 3.38 - 3.32 ppm (2H). Achiral dirhodium(II) tetracarboxylate catalysts were used in screening.

Example 2 - Optimization of low Rh(II) Catalyst loading

Scheme 3 Boc

[0129] Driven by the high and variable cost of rhodium, a significant challenge of conducting the cyclopropanation with a much lower catalyst loading was overtaken. Therefore, it was determined that a catalyst loading of 0.005 mol % would be an appropriate target because at such low catalyst loading, the fluctuating cost of rhodium would not be especially impactful on the overall cost of the process. The results of the optimization study are summarized in Table 4. When the reaction was conducted at ambient temperature, exo/endo was produced in low yield (entry 1 on Table 4). In the case of the donor/acceptor carbenes, the optimum temperature for high turnover numbers (TON) was 60-70 °C. (See For Example, Wei, B.; Sharland, J. C.; Blackmond, D. G.; Musaev, D. G.; Davies, H. M. L. In Situ Kinetic Studies of Rh(II)-Catalyzed C-H Function-alization to Achieve High Catalyst Turnover Numbers. ACS Catalysis 2022, 12 (21), 13400-13410. DOI: 10.1021/acscatal.2c04115. Wei, B.; Sharland, J. C.; Lin, P.; Wilkerson-Hill, S. M.; Fullilove, F. A.; McKinnon, S.; Blackmond, D. G.; Davies, H. M. L. In Situ Kinetic Studies of Rh(II)-Catalyzed Asymmetric Cyclopropanation with Low Catalyst Loadings. ACS Catalysis 2020, 10 (2), 1161-1170. When the reactions with ethyl diazoacetate were conducted at 70 °C, the yields of the cyclopropanation were still relatively low (9-32%) and the crude NMR showed evidence of unreacted ethyl diazoacetate (entries 2-5). The optimum catalyst in this study was the bridged dicarboxylate catalyst Rh₂(esp)₂.

[0130] Further optimization of the Rh₂(esp)₂-catalyzed was conducted at 90 °C and under these conditions the yield of exo/endo greatly improved to 76% (entry 8, Table 4). As these reaction temperatures are relatively high, control experiments were conducted in the absence of the catalysts (entries 12 and 13, Table 4), which revealed the products are not being formed under purely thermal conditions because the ethyl diazoacetate remained unchanged. The reaction was scaled up to a gram scale and as is typical of this chemistry, the isolated yield was significantly improved in the larger scale reaction (90%, entry 14, Table 4). Ethyl diazoacetate, dissolved in toluene, was also evaluated as the carbene source, but this was an inferior (entry 15, Table 4) because the carbene had a competing reaction with toluene in addition to the desired cyclopropanation. TABLE 4.

Entries 14 and 15 are gram scale synthesis.

[0131] Reactions in Table 4 were run at 0.500 mmol. Diastereomeric ratio (d.r.) was calculated from crude ¹HNMR. TON (Turn over number) was calculated by [(1 equivalent of limiting reagent / x equivalent of catalyst)] x [(% yield / 100)].

Example 3 - Endo/Exo Selectivity

Scheme 4

[0132] Experiments were directed towards exploring whether the diastereoselectivity of the process could be directed towards the thermodynamically less favorable endo diastereomer (Table 5). The achiral catalysts were relatively unselective, resulting in close to a 1 : 1 diastereomeric ratio. However, when the reaction was conducted using chiral catalysts, conditions were discovered where the endo product predominated by up to 83:17 diastereomeric ratio. Furthermore, this reaction could readily be conducted on gram scale with similar performance.

[0133] As shown from Table 5, the diastereoselectivity of the cyclopropanation process can be controlled towards the thermodynamically less favor diastereoisomer using catalysts Rh₂(S-TPPTTL)₄ and its brominated derivative, Rh₂[5-tetra-(3,5-di- Br)TPPTTL]4 with high yields.

TABLE 5.

gram-scale synthesis [0134] Reactions on Table 5 were run at 0.500 mmol. The yield is ¹HNMR yield analysis with 1,3,5-trimethoxybenzene. Diastereomeric ratio was calculated from crude ¹HNMR. TON was calculated by [(1 equivalent of limiting reagent / x equivalent of catalyst)] x [(% yield / 100)].

Example 4 - Exo/ Endo Isomerization

Scheme 5

[0135] Reactions were performed to explore how to generate the exo isomer of the product. This was achieved by conducting a base induced epimerization (Table 6). The best conditions were found to be either sodium or potassium tert-butoxide in THF (entries 1, 2, 5) Under these conditions, complete equilibration to the exo isomer was observed. Although these conditions also caused partial transesterification, the next step calls for hydrolysis of the esters. The optimum conditions were potassium tert-butoxide in THF.

[0136] The exo diastereoisomer can be obtained exclusively by treatment of a 1 : 1 mixture of exo/endo with sodium tert-butoxide by epimerization at the a-carboxylate stereocenter of the thermodynamically less favored endo isomer, followed by hydrolysis with aqueous sodium hydroxide and alcoholic solvent.

Table 6.

Example 5 - Selective Hydrolysis to Afford Endo Acid

[0137] Conditions were explored to selectively hydrolyze the exo isomer to lead to the clean formation of the endo isomer (Table 7). These studies were conducted on material that was a 49:51 mixture of exo and endo isomers. Aqueous sodium hydroxide in ethanol was found to be very effective, leaving the product highly enriched in the endo isomer (as seen with entries 7 and 8, Table 7).

Scheme 6

Table 7.

[0138] Recovered % yield was calculated by ([yield % / 51 endo\ x [(product endo d.r.)/(product endo d.r. + product exo d.r.)]). D.r. was calculated from ¹HNMR by integrating broad multiplet at 2.10 - 2.02 ppm (exo 2H) & multiplet 1.89 - 1.82 ppm (endo 2H).

Example 6 - Optimization of Time

[0139] Scheme 7 shows strategies to selectively access to exo- or endo-acids. In one hand, a one-pot procedure (isomerization/hydrolysis) was performed to access exo-2- aza-[3.1.0]-bicyclohexane-6-carboxylate (exo- acid). On the other hand, a mixture of bicyclic system enriched in the endo isomer by a 17:83 exo'.endo ratio (Table 5, entry 12) can be converted to exclusively the endo isomer by changing the reaction sequence. Therefore, treatment of the bicyclic mixture (exo/ endo) with aqueous sodium hydroxide results in the selective hydrolysis of the exo-ester, and the resulting endo can be obtained cleanly after extractions as a single diastereomer. An extended exposure of endo-ester to aqueous sodium hydroxide gives the clean formation of the endo-acid (endo-2aza-[3.1.0]- bicyclohexane-6-carboxylate).

Scheme 7

[0140] A further study was conducted on the selective hydrolysis starting with material that was already 83:17 (endoiexo) (Table 5, entry 12). The optimum conditions were found to be 30 min at ambient temperature as this led to complete hydrolysis of the exo isomer, resulting in a 58% yield of recovered endo >30: 1 d.r. (entry 2, Table 8).

Table 8.

Example 7 - Amidation Reactions

Scheme 8

[0141] A is H or an organic protecting group such as tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), or fluorenylmethyloxycarbonyl (Fmoc), tosyl (Tos), nosyl (Ns), and any other carbonyl or sulfonyl groups.

[0142] Y is covalent bond, O, S, C₁ to C₆ ether, or C₁ to C₆ thioether,

[0143] Z is null, a covalent bond, CH₂, or CH₂CH₂,

[0144]

is an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C6 to CIO aryl, is substituted with one or more Rn,

and

[0145] Each R_n is independently OH, F, Cl, Br, I, NH₂, CF₃, C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, C₁ to C₇ ether, or C₁ to C₇ thioether.

[0146] The protected amine carboxylic acid compound such as (1R,5S,6r)-3- tosy1-3-azabicyclo[3.1.0]hexane-6-carboxylic acid or (1R,5S)-3-(tert-butoxycarbonyl)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid is reacted with an amine compound such as 2- methyl- 1 -((3 -methylpyridin-2-yl)oxy)propan-2-amine, 2-( 1 -methyl - 1 H-indazo1-3 - yl)propan-2 -amine, or other amines shown on Table 1 in the presence of base such as DMAP, and triethylamine, a solvent such as THF in an amide coupling reaction to give the compound of Formula A or Formula B. One skilled in the art will recognize that there are many catalyst, ligand, base, and solvent combinations that may be used to perform this transformation. ( 1 R, 5 S, 6r)-3 -tosy1-3 -azabicyclo [3.1.0]hexane-6-carbonyl chloride

[0147] To a flame-dried round-botom flask was added (1R,5S,6r)-3-tosy1-3- azabicyclo[3.1.0]hexane-6-carboxylic acid (563 mg, 1 equiv, 2.00 mmol), toluene (184 mg, 6.25 mL, 0.32 molar, 1 equiv, 2.00 mmol), oxalyl chloride (381 mg, 263 gL, 1.5 equiv, 3.00 mmol), and then DMF (14.6 mg, 15.5 μL, 0.1 equiv, 200 μmol). The vessel was capped with a nitrogen balloon. The reaction vessel was stirred and heated to 45 °C for 4 h. After the elapsed time, the reaction mixture was concentrated in vacuo at 45 °C and redissolved in THF (144 mg, 6.25 mL, 0.32 molar, 1 equiv, 2.00 mmol) as a 0.32 M stock solution and used in the presence of an amine (next step).

(1R,5S,6r)-N-(bicyclo[l.l.l]pentan-1-yl)-3-tosy1-3-azabicyclo[3.1.0]hexane-6- carboxamide

[0148] To an 8 mL vial charged with a stir-bar was added bicyclo[ 1.1.1 ]pentan- 1 - aminium chloride (32.9 mg, 1.1 equiv, 275 μmol) and DMAP (3.05 mg, 0.1 equiv, 25.0 μmol). The reaction mixture was cooled with a saltwater ice bath. Once cooled, to the mixture was added triethylamine (101 mg, 139 μL, 4 equiv, 1.00 mmol) and then a chilled solution of (1R,5S,6r)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carbonyl chloride (74.9 mg, 781 μL, 0.32 molar, 1 equiv, 0.250 mmol) was added to the mixture. The reaction mixture was stirred and allowed to warm to room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with a 1 : 1 mixture of ethanol: deionized water and chilled in a -20 °C fridge for at least an hour. The chilled suspension was filtered through a fine porosity slow flowrate filter paper under vacuum and the filter cake was vacuum dried to afford (1R,5S,6r)-N- (bicyclo[l.l.l]pentan-1-yl)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carboxamide (52 mg, 0.15 mmol, 60 % yield) as a tan powder.

[0149] ¹H NMR (400 MHz, CDCl₃) 7.67 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.00 (s, 1H), 3.59 (d, J = 9.5 Hz, 2H), 3.03 (dd, J = 9.4, 1.7 Hz, 2H), 2.44 (s, 3H), 2.43 (s, 1H), 2.07 (s, 6H), 1.96 (d, J = 2.9 Hz, 2H), 1.43 (t, J = 3.1 Hz, 1H); HRMS (+p APCI) Calcd. for C₁₈H₂₃O₃N₂ ³²S [M + H]+: 347.14239, Found: 347.14292.

(1R,5S,6r)-N-(2-methylbut-3-yn-2-yl)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0150] To an 8 mL vial charged with a stir-bar was added 2-methylbut-3-yn-2- amine (22.9 mg, 1.1 equiv, 275 μmol ) and DMAP (1.53 mg, 0.05 equiv, 12.5 μmol). The reaction mixture was cooled with a saltwater ice bath. Once cooled, to the mixture was added triethylamine (75.9 mg, 105 °L, 3 equiv, 750 μmol) and then a chilled solution of (1R,5S,6r)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carbonyl chloride (74.9 mg, 781 μL, 0.32 molar, 1 equiv, 0.250 mmol) was added to the mixture. The reaction mixture was stirred and allowed to warm to room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with a 1 : 1 mixture of ethanokdeionized water and chilled in a -20 °C fridge for at least an hour. The chilled suspension was filtered through a fine porosity slow flowrate filter paper under vacuum and the filter cake was vacuum dried to afford (1R,5S,6r)-N-(2-methylbut-3-yn-2-yl)-3- tosy1-3-azabicyclo[3.1.0]hexane-6-carboxamide (59 mg, 0.17 mmol, 68 % yield) as a cream powder.

[0151] ¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.76 (s, 1H), 3.61 (d, J = 9.5 Hz, 2H), 3.03 (dt, J = 9.4, 1.7 Hz, 2H), 2.44 (s, 3H), 2.33 (s, 1H), 1.98 (s, 2H), 1.61 (s, 6H), 1.48 (t, J = 3.1 Hz, 1H); HRMS (+p APCI) Calcd. for C₁₈H₂₃O₃N₂ S [M + H]+: 347.14239, Found: 347.14272.

(2-oxa-6-azaspiro[3.3]heptan-6-yl)((1R,5S,6r)-3-tosy1-3-azabicyclo[3.1.0]hexan-6- yl)methanone

[0152] To an 8 mL vial charged with a stir-bar was added 2-oxa-6- azaspiro[3.3]heptane (27.3 mg, 1.1 equiv, 275 μmol) and DMAP (1.53 mg, 0.05 equiv, 12.5 gmol). The reaction mixture was cooled with a saltwater ice bath. Once cooled, to the mixture was added triethylamine (75.9 mg, 105 μL, 3 equiv, 750 μmol) and then a chilled solution of (1R,5S,6r)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carbonyl chloride (74.9 mg, 781 μL, 0.32 molar, 1 equiv, 0.250 mmol) was added to the mixture. The reaction mixture was stirred and allowed to warm to room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo at 55 °C. The neat material was resuspended with a 1:4 mixture of ethanokdeionized water and chilled in a -20 °C fridge for at least an hour. The chilled suspension was filtered through a fine porosity slow flowrate filter paper under vacuum and the filter cake was vacuum dried to afford (2-oxa-6-azaspiro[3.3]heptan-6- yl)((1R,5S,6r)-3-tosy1-3-azabicyclo[3.1.0]hexan-6-yl)methanone (58 mg, 0.16 mmol, 64 % yield) as a tan powder.

[0153] ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.95 - 4.66 (m, 4H), 4.33 (s, 2H), 4.11 (s, 2H), 3.60 (d, J = 9.7 Hz, 2H), 3.04 (dt, J = 9.7, 1.7 Hz, 2H), 2.45 (s, 3H), 1.95 (d, J = 3.0 Hz, 2H), 1.50 (t, J = 3.1 Hz, 1H); HRMS (+p APCI) Calcd. for C C₁₈H₂₃O₄N₂ ³²S [M + H]+: 363.1373, Found: 363.13733.

(1R,5S,6r)-N-(6-chloropyridin-2-yl)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0154] To an 8 mL vial charged with a stir-bar was added 6-chloropyridin-2- amine (35.4 mg, 1.1 equiv, 275 μmol ) and DMAP (1.53 mg, 0.05 equiv, 12.5 μmol). The reaction mixture was cooled with a saltwater ice bath. Once cooled, to the mixture was added triethylamine (75.9 mg, 105 μL, 3 equiv, 750 μmol) and then a chilled solution of (1R,5S,6r)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carbonyl chloride (74.9 mg, 781 μL, 0.32 molar, 1 equiv, 0.250 mmol) was added to the mixture. The reaction mixture was stirred and allowed to warm to room temperature. The reaction mixture was then diluted with a 1 : 1 mixture of ethanoldeionized water and chilled in a -20 °C fridge for at least an hour. The chilled suspension was filtered through a fine porosity slow flowrate filter paper under vacuum and the filter cake was vacuum dried to afford (1R,5S,6r)-N-(6- chloropyridin-2-yl)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carboxamide (67 mg, 0.17 mmol, 68 %) as a tan powder.

[0155] ¹H NM (R400 MHz, CDCl₃) [as a mixture of rotamers/tautomers] δ 8.00 (d, J = 8.2 Hz, 1H), 7.94 (s, 1H), 7.82 (t, J = 7.8 Hz, 0.5H), 7.70 (d, J = 8.2 Hz, 2H), 7.67 - 7.57 (m, 3H), 7.41 (d, J = 8.0 Hz, 0.5H), 7.35 (dd, J = 18.7, 8.0 Hz, 4H), 7.18 (d, J = 7.7 Hz, 0.5H), 7.05 (d, J = 7.7 Hz, 1H), 3.65 (d, J = 9.9 Hz, 2H), 3.56 (d, J = 9.7 Hz, 2H), 3.20 - 3.13 (m, 2H), 3.07 (d, J = 9.4 Hz, 2H), 2.48 (s, 3H), 2.44 (s, 3H), 2.18 (d, J = 2.8 Hz, 2H), 2.11 (d, J = 2.9 Hz, 2H), 2.01 (t, J = 3.1 Hz, 1H), 1.54 (t, J = 3.1 Hz, 1H);

HRMS (+p APCI) Calcd. for C₁₈H₁₉O₃N3³⁵Cl³²S [M + H]+: 392.08302, Found: 392.08283.

(1R,5S,6r)-N-(thiazo1-2-yl)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0156] To an 8 mL vial charged with a stir-bar was added thiazo1-2-amine (27.5 mg, 1.1 equiv, 275 μmol) and DMAP (1.53 mg, 0.05 equiv, 12.5 μmol). The reaction mixture was cooled with a saltwater ice bath. Once cooled, to the mixture was added triethylamine (75.9 mg, 105 μL, 3 equiv, 750 gmol) and then a chilled solution of (1R,5S,6r)-3-tosy1-3-azabicyclo[3.1.0]hexane-6-carbonyl chloride (74.9 mg, 781 μL, 0.32 molar, 1 equiv, 0.250 mmol) was added to the mixture. The reaction mixture was stirred and allowed to warm to room temperature. The reaction mixture was then diluted with a 1 : 1 mixture of ethanokdeionized water and chilled in a -20 °C fridge for at least an hour. The chilled suspension was filtered through a fine porosity slow flowrate filter paper under vacuum and the filter cake was vacuum dried to afford (1R,5S,6r)-N-(thiazo1-2-yl)- 3-tosy1-3-azabicyclo[3.1.0]hexane-6-carboxamide (57 mg, 0.16 mmol, 63 % yield) as a tan powder.

[0157] R (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H),

7.53 - 7.41 (m, 3H), 7.18 (d, J = 3.6 Hz, 1H), 3.48 (d, J = 9.6 Hz, 2H), 2.98 (dt, J = 9.5, 1.6 Hz, 2H), 2.42 (s, 3H), 2.13 (t, J = 3.1 Hz, 1H), 2.06 (d, J = 2.8 Hz, 2H); HRMS (+p APCI) Calcd. for C₁₆H₁₈O₃N₃ ³² [M + H]+: 364.07841 , Found: 364.07847.

Example 8 - Deprotection Reactions

Scheme 9

[0158] A is an organic protecting group, Y, Z,

and R_n are as previously defined.

[0159] The compound of Formula C is converted to Formula D through amine deprotection mechanism well known in the art, such as use of a strong acid (e.g., in deprotecting Boe, or tosyl), or strong base (e.g., in deprotecting Fmoc), catalytic hydrogenation (e.g., in deprotecting cBz). One skilled in the art will recognize that there are many reagents, bases, acids, and solvent combinations that may be used to perform this kind of deprotection.

Claims

CLAIMS We claim:

1. A method for preparing a compound of the formula:

the method comprising: mixing a compound of the formula

with a compound of the formula in the presence of from about 0.0001 to about 1 mol% Rh catalyst,

wherein A is H or an organic protecting group,

X is OH, O-R_x, NH₂, NH(R_x), N(R_x)₂, or a halogen, and

R_x is C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens.

2. The method of claim 1, wherein the compound is

salt thereof.

3. The method of claim 1, wherein the compound is

salt thereof.

4. The method of any one of claims 1 to 3, wherein A is tert-butyloxycarbonyl

(Boc), tosyl (Tos), carbobenzyloxy (Cbz), or fluorenylmethyloxycarbonyl (Fmoc).

5. The method of any one of claims 1 to 4, wherein X is OH or O-R_x.

6. The method of any one of claims 1 to 5, wherein X is O-R_x and R_x is C₂ alkyl.

7. The method of any one of claims 1 to 6, wherein the Rh catalyst is of the formula Rh₂(L)₂ or Rh₂(L)₄, and L is a ligand.

8. The method of any one of claims 1 to 7, wherein the Rh catalyst is of the formula Rh₂(L)₂ or Rh₂(L)₄, and wherein L is acetate (OAc), pivalate (OPiv), octanoate (Oct), triphenylacetate (TP A), or 3-[3-(2-carboxy-2-methylpropyl)phenyl]-2,2- dimethylpropanoic acid (esp).

9. The method of claim 2, wherein the Rh catalyst is of the formula:

10. The method of claim 3, wherein the Rh catalyst is of the formula:

wherein each

is a C₅ to C₈ aryl, optionally substituted with from 1 to 3 halogens or a C₅ to C₆ heteroaryl with from one to 1 heteroatoms selected from N, O, or S, optionally substituted with from 1 to 3 halogens.

11. The method of claim 10, wherein the Rh catalyst is Rh₂[S'-tetra-(3,5-di- Br)TPPTTL]₄.

12. The method of any one of claims 1 to 11, wherein the Rh catalyst is present in an amount of from about 0.0001 to about 0.1 mol%.

13. The method of any one of claims 1 to 12, wherein the Rh catalyst is present in an amount of about 0.005 mol%.

14. The method of any claim 9, wherein the method further comprises an isomerization step of the formula:

the isomerization step comprises treatment with a strong base.

15. The method of claim 14, wherein the strong base comprises sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, 1,8 -Diazabicyclo [5.4.0]undec-7-ene (DBU), triazabicyclodecene (TBD), or 2-tert-Buty1-1,1,3,3-tetramethylguanidine (BTMG).

16. The method of claim 11, wherein the method further comprises a selective hydrolysis step of the formula:

wherein the selective hydrolysis step comprises treatment with a base in a polar protic solvent.

17. The method of claim 16, wherein the base is sodium hydroxide or potassium hydroxide.

18. The method of claim 16 or 17, wherein the polar protic solvent comprises ethanol, methanol, isopropanol, aqueous ethanol, aqueous methanol, aqueous isopropanol, or combinations thereof.

19. The method of any one of claims 16 to 18, wherein the selective hydrolysis step comprises an extraction with a nonpolar solvent.

20. The method of claim 19, wherein the nonpolar solvent comprises w-hexane.

21. A method for preparing a compound of the formula:

pharmaceutically acceptable salts thereof, wherein

Y is covalent bond, O, S, C₁ to C₆ ether, or C₁ to C₆ thioether,

Z is null, a covalent bond, CH₂, or CH₂CH₂, is an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the

heteroaryl or C₆ to C₁₀ aryl,

substituted with one or more R_n, and each R_n is independently OH, F, Cl, Br, I, NH₂, CF₃, C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, C₁ to C₇ ether, or C₁ to C₇ thioether, the method comprising:

(i) mixing a compound of the formula

a compound of the formula

in the presence of from about 0.0001 to about 1 mol% Rh catalyst to form an intermediate compound of the formula:

wherein A is H or an organic protecting group,

X is OH, O-R_x, NH₂, NH(R_x), N(R_x)₂, or a halogen, and R_x is C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens;

(ii) mixing the intermediate compound with

to yield

22. The method of claim 21, wherein the compound is of the formula:

or pharmaceutically acceptable salts thereof.

23. The method of claim 21 or 22, wherein the compound is of the formula:

cally acceptable salt thereof.

24. The method of claim 21 or 22, wherein the compound is of the formula:

pharmaceutically acceptable salt thereof.

25. The method of any one of claims 21 to 24, wherein the Rh catalyst is of the formula:

26. The method of any one of claims 21 to 25, wherein the Rh catalyst is present in an amount of about 0.005 mol%.

27. The method of any one of claims 21 to 26, wherein step (i) further comprises an isomerization step of the formula:

, wherein the isomerization step comprises treatment with a strong base.

28. The method of claim 27, wherein the strong base comprises sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, 1,8-Diazabicyclo [5.4.0]undec-7-ene (DBU), triazabicyclodecene (TBD), or 2-tert-Buty1-1,1,3,3-tetramethylguanidine (BTMG).

29. A compound of the formula:

salt thereof, wherein A is H or an organic protecting group, X is OH, O-R_x, NH₂, NH(R_x), (NR_x)₂ or a halogen, and R_x is C₁-C₆ alkyl, optionally substituted with from 1 to 6 halogens, and the compound is prepared by the method of claim 1.

30. The compound of claim 29, wherein A is tert-butyloxycarbonyl (Boc), X is O-R_x, and R_x is C₂ alkyl.

31. A compound of the formula:

pharmaceutically acceptable salt thereof, wherein the compound is prepared by the method of claim 1